In vivo effects of AZD4547, a novel Fibroblast Growth Factor Receptor Inhibitor (FGFRI), in a mouse model of endometriosis.

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Abstract

Endometriosis is a chronic disease, characterised by the growth of endometrial-like cells outside the uterine cavity. Due to its complex pathophysiology, a totally resolving cure is yet to be found. The aim of this study was to compare the therapeutic efficacy of AZD4547, a novel fibroblast growth factor receptor inhibitor (FGFRI), with a well characterised progestin, etonogestrel (ENG) using a validated in vivo mouse model of endometriosis. Endometriosis was induced by transplanting uterine fragments from donor mice in proestrus into the peritoneal cavity of recipient mice, which then developed into cyst-like lesions. AZD4547 and ENG were administered systemically either from the day of endometriosis induction or 2 weeks post-surgery. After 20 days of treatment, the lesions were harvested; their size and weight were measured and analysed histologically or by qRT-PCR. Stage of oestrous cycle was monitored throughout. Compared to vehicle, AZD4547 (25mg/kg) was most effective in counteracting lesion growth when treating from day of surgery and 2 weeks after; ENG (0.8mg/kg) was similarly effective in reducing lesion growth but only when administered from day of surgery. Each downregulated FGFR gene expression (p<0.05). AZD4547 at all doses and ENG (0.008mg/kg) caused no disturbance to the oestrous cycle. ENG at 0.08mg/kg and 0.8mg/kg was associated with partial or complete oestrous cycle disruption and hyperaemia of the uteri. AZD4547 and ENG both attenuated endometriotic lesion size but only AZD4547 did not disrupt the oestrous cycle, suggesting that targeting of fibroblast growth factor receptor (FGFR) is worthy of further investigation as a novel treatment for endometriosis.

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Original languageEnglish
JournalPharmacology research & perspectives
Publication statusAccepted/In press - 20 Nov 2020

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